Tilapia Head Glycolipid Alleviates Indomethacin-Induced Gastric Ulcer via Regulating Oxidative Stress and Inflammation Through COX/PGE2 Signaling Pathway in Adult Rats

The aim of this experiment was to investigate the ameliorative effect and molecular mechanism of tilapia head glycolipid(TH-GL)on indomethacin(IDM)-induced gastric ulcer in male Sprague Dawley(SD)rats.The gastric ulcer model was established by oral administration of 30mgkg^(-1) IDM after 7 days of TH-GL or omeprazole(OME)administration in rats.Then the macroscopic gastric injury symptoms,gastric mucosa protective factor cyclooxygenase 1(COX-1),cyclooxygenase 2(COX-2),prostaglandin E_(2)(PGE_(2)),the levels of oxidative stress,and inflammatory cytokine expression levels in the rats were analyzed.The experimental results showed that multiple ulcers appeared on the gastric surface of the rats in the model group.Compared to the model group,TH-GL significantly alleviated gastric ulcers and reduced the gastric damage index in rats.In addition,TH-GL significantly promoted the expression of constitutive enzyme COX-1 while inhibited the expression of inducible enzyme COX-2,and make PGE2 maintain at normal levels.TH-GL also inhibited oxidative stress and inflammatory responses,increased superoxide dismutase(SOD)activity and glutathione(GSH)content,decreased the level of malondialdehyde(MDA)and the content of pro-inflammatory factor.In conclusion,these results suggested that TH-GL could maintain the expression levels of COX-1 and PGE2 while inhibit the expression of COX-2 in the gastric of rat and then prevent IDM-induced gastric ulcer,which may be related to the regulation of oxidative stress and inflammatory response.Therefore,TH-GL might be a new option for the prevention of gastric diseases induced by IDM.

Homopterocarpin contributes to the restoration of gastric homeostasis by Pterocarpus erinaceus following indomethacin intoxication in rats

Objective:To investigate the restorative effect of Pterocarpus erinaceus(P.erinaceus) and homopterocarpin.an isoflavonoid isolated from it.on indomethacin-indueed disruption in gastric homeostasis in rats.Methods:Adult rats were dn ided into five groups and lasted for 48 h before treatment.Group I received olive oil(vehicle),group 2 received 25 ing/kg indomethaein while groups 3-5 received cimetidine(100 mg/kg).lioniopterocarpin(25 mg/kg) and P.erinaceus ethanolie stem hark extract(100 mg/kg) respectively.After 1 h.all the groups except group 2 were administered 25 mg/kg of indomethacin.One hour later,the rats were sacrificed and the ulcer index and other gaslroprotective indices were evaluated.Results:Indomethacin caused significant injury to the stomach of the rats as reflected in the ulcer indices(9.0±1.4) as compared with that of control(2.0±0.0).Equally,there were significant increases in gastric acid concentration and malondialdehvde level in the stomachs of the ulcerated animals compared with the control.However mucus content,reduced gluthatione level and gastric pH were significantly reduced in the ulcerated animals compared with the control.Pretreatment with either Pterocarpus bark extract or homopterocarpin reversed the effects of indomethaein on the evaluated parameters.Conclusions:These results indicate that both homopterocarpin and Plerocarpus extract offered gastroprotection against indomethacin-induced ulcer by antioxidative mechanism and the modulation of gastric homeostasis.The results also suggest that homopterocarpin might he responsible for.or contribute to the antiulcerogenic property of P.erinaceus.

Alginate encapsulated mesoporous silica nanospheres as a sustained drug delivery system for the poorly water-soluble drug indomethacin

We applied a combination of inorganic mesoporous silica material,frequently used as drug carriers,and a natural organic polymer alginate(ALG),to establish a sustained drug delivery system for the poorly water-soluble drug Indomethacin(IND).Mesoporous silica nanospheres(MSNs)were synthesized using an organic template method and then functionalized with aminopropyl groups through postsynthesis.After drug loading into the pores of aninopropyl functionalized MSNs(AP-MSNs),IND loaded AP-MSNs(IND-AP-MSNs)were encapsulated by ALG through the ionic interaction.The effects of surface chemical groups and ALG layer on IND release were systematically studied using scanning electron microscopy(SEM),transmission electron microscopy(TEM),nitrogen adsorption,zetapotential analysis and TGA analysis.The surface structure and surface charge changes of the ALG encapsulated AP-MSNs(ALG-AP-MSNs)were also investigated.The results showed that sustained release of IND from the designed drug delivery system was mainly due to the blockage effect from the coated ALG.We believe that this combination will help designing oral sustained drug delivery systems for poorly water-soluble drugs.

Aloe vera attenuated gastric injury on indomethacin-induced gastropathy in rats

AIM:To evaluate the protective effects of Aloe vera on gastric injury in rats with indomethacin(IMN)-induced gastropathy.METHODS:Male Sprague-Dawley rats were randomly divided into three groups.Group 1(control,n=6)was given distilled water(DW)orally.Group 2(IMN,n=6)was given oral IMN(150 mg/kg)dissolved in5%sodium bicarbonate(Na HCO3-)at time 0 and 4 h.Group 3(Aloe vera-treated,n=6)was given oral Aloevera(150 mg/kg)dissolved in DW and IMN at time 0and 4 h.Eight hours later,the stomach was removed to determine gastric malondialdehyde(MDA),the number of interleukin(IL)-18 positive stained cells(%)by immunohistochemistry,and for histopathological examination.Then,the serum was collected to determine tumor necrosis factor(TNF)-αand cytokineinduced neutrophil chemoattractant(CINC)-1 by sandwich enzyme linked immunosorbent assay method.RESULTS:In the IMN group,serum TNF-α,CINC-1and gastric MDA were significantly increased when compared to the control group(27.78±1.52 pg/m L vs 85.07±49.11 pg/m L,P=0.009;104.55±45.80pg/m L vs 1054.70±20.38 pg/m L,and 1.74±0.21nmol/mg vs 9.36±1.07 nmol/mg protein,P=0.000,respectively).The mean level of TNF-α,CINC-1 and gastric MDA in the Aloe vera-treated group were improved as compared with the IMN group(85.07±49.11 pg/m L vs 35.19±1.61 pg/m L,P=0.021;1054.70±20.38 pg/m L vs 813.56±239.04 pg/m L,P=0.025;and 9.36±1.07 nmol/mg vs 2.67±0.64 nmol/mg protein,P=0.000,respectively).The number of IL-18 positive stained cells(%)in the gastric epithelial cells of the IMN group was significantly higher than the control group(5.01%±3.73%vs 30.67%±2.03%,P=0.000,respectively).In contrast,Aloe vera treatment decreased the number of IL-18 positive stained cells(%)significantly when compared with the IMN group(30.67%±2.03%vs 13.21%±1.10%,P=0.000,respectively).Most rats in the IMN group developed moderate to severe gastric inflammation and erosions.The gastric erosions and neutrophil infiltration scores were significantly reduced in the Aloe veratreated group.CONCLUSION:Aloe vera attenuated IMN-induced gastropathy in rats by the reduction of oxidative stress,inflammation,and improvement of gastrichistopathology.

Pre-Clinical Experimental Studies of Indomethacin-Releasing Copper Intrauterine Device

Effects of two types of intrauterine device (IUD) on the prostaglandins and endothelin (ET) in uterus and on the endometrial morphology in rats and rabbits, and Cu 2+ releasing amounts of both IUDs in vitro were observed. The results showed that the inhibiting action of the indomethacin releasing copper IUD (FICu IUD) on the PGI 2 was stronger than that on the TXA 2, the ratio of 6 keto PGF 1α /TXB 2 was reduced with the increase of the doses. There were significant differences between the groups. The FICu IUD could inhibit the rising of the ET level and lighten the endometrial impairment caused by the FCu IUD, and promote copper ion release. It was suggested that indomethacin released by FICu IUD could effectively reduce abnormal uterine bleeding.

Optimization of indomethacin loaded nanostructured lipid carriers

Topical administration is the most common and acceptable use for the treatment of ocular disease.However,the major problem of ocular drug delivery is the rapid drug elimination from the pre-ocular area leading to poor ocular bioavailability[1].Nanostructure lipid carriers(NLC)possess a significant enhancement in ocular bioavailability by increasing the permeability and mucoadhesive property[2].In this study,indomethacin(IND),non-steroidal anti-inflammatory,was used as a model drug[3].

Protective effect of Nigella sativa L.to gastric mucous of indomethacin-induced gastric ulcer rats

OBJECTIVE To investigate the effect of Nigella sativa L.as gastric protective on indomethacin-induced rats.METHODS the design of this research is randomized post test control group design.The rats were randomly divided into 5 groups which 5 rats in each.Rats were fasted for 8h before treatment.The first group was a control group(only gave aquadest as vehicle orally).The second group was subjected to induced with indomethacin 30mg·kg-1.The rest groups were subjected to induced by indomethacin and methanolic extract of Nigella sativa L.200,300 and 400mg·kg-1 every 8h for 24 h,respectively,for third,fourth and fifth group.Rats were sacrificed after anesthetized with ketamine and gastric were washed before observed.Macroscopic observation based on a score of lesion and microscopic observation on gastric based by histological HE staining.Whole data were analysis of an ANOVA statistical program.RESULTS The administration of Nigella sativa L.significantly decreased gastric ulcer macroscopically starting at dose 100,200 and 300mg·kg-1(P<0.05).Microscopic observation showed significant decreasing at dose 200 and 300mg·kg-1(P<0.05).Interestingly,there was no significant different between control and dose 300mg·kg-1.Negative correlation between lesion and doses were-0.919,-0.953 for macroscopic and microscopic lesion respectively.It means there was strong correlation between dose and lesion,higher dose lesser lesion.The mechanism of gastric protective of NigellasativaL.may caused by the bioactive compound such as thymoquinone which known as antiinflammation and antioxidant.CONCLUSION Methanolic extract of Nigella sativa L.decreased peptic ulcer both macroscopic and microscopic conditions on indomethacin-induced rats.

Synthesis of Indomethacin Conjugates with D-Glucosamine

Two series of indomethacin conjugates with D-glucosamine were prepared with theobjectives of reducing ulcerogenic potency, increasing the bioavailability of indomethacin andexerting the coordinative effects on osteoarthritis. The structures of the conjugates were identifiedby H NMR and C NMR. The ester conjugates inhibited edema as potent as indomethacin. 1 13

The Multi-Center Comparative Clinical Trial of the Second Generation of Indomethacin VCu and TCu380A

Objective To study the effectiveness and side effects of the modified new indomethacin VCu IUD Material & methods It is a randomized multi-center clinical trial. Indomethacin VCu and TCu380A were inserted in 2 000 healthy women in 6 clinical units including urban and rural area from May 1997 to Feb 1998, with 1 000 cases in each group. Follow up time were 6, 12, and 24 month after insertion. Results The clinical characteristics of subjects in two groups were similar. Follow up was completed in 98.25% of cases. The net cumulative continuous rate at 6 month was 95.5% in TCu380A group and 97.5% in Indomethacin VCu group (P<0.05); at 12 month it was 93.79% and 94.78% respectively; at 24 month it was 88.23% and 89.77% respectively. The expulsion rate was higher in T group than in V group during 24 months. Termination due to pregnancy and bleeding or pain was similar in two groups. The occurrence of menorrahgia, prolonged bleeding and abdominal pain was also higher in T group than that in V group during 24 months after insertion. Spotting was more often in T group in 12 month. On the other hand, more subjects complained hypomenorrhea in V group. The total B/S period, average B/S period and the longest B/S period were all longer in T group during 4～6 month after IUD insertion (P< 0.01). The amount of hemoglobin was similar in two groups before IUD insertion. At the end of study, the amount of hemoglobin in T group decreased compared with baseline (P<0.001), and was lower than V group at the same time (P<0.001), while no change was observed in V group. Conclusion Compared with TCu380A, the second generation of indomethacin VCu possess the same contraceptive effect and cumulative continuous rate and lower side effects such as bleeding and abdominal pain. VCu is more beneficial to reproductive health of women, therefore, is worth of clinical application.

Immunoregulatory Effects of Indomethacin on Rats with Trauma

In this article, we invertigated changes of immune functions and immunoregulatory effects of indomethacin on rats with trauma. The results show that spontaneous suppressor T cell activity of spleen significantly increased and Interleukin 2 production and DNA synthesis capacity of splenocytes markedly decreased in rats with trauma. Indomethacin could markedly improve immune function , decreased spontancous suppressor T cell activity and prompted Interleukin 2 production and DNA synthesis capacity of splenocytes.

Herb-drug interaction in the protective effect of Alpinia officinarum against gastric injury induced by indomethacin based on pharmacokinetic, tissue distribution and excretion studies in rats

Alpinia officinarum Hance of the Chinese traditional herb for the treatment of emesis, abdominal pain and diarrhea has been used to counteract gastric disease induced by indomethacin in rats without obvious side effects. However, the role of herb-drug interaction between indomethacin and A. officinarum based on pharmacokinetic, tissue distribution and excretion still remains unknown. In this study, an ultra-fast liquid-tandem mass spectrometry(UFLC-MS/MS) method was developed for simultaneous determination of indomethacin and its three metabolites, O-desmethylindomethacin(ODI), deschlorobenzoylindomethacin(NDI) and indomethacin acyl-b-D-glucuronide(IDAbG) by oral administration of indomethacin solution with and without the ethanolic extract of A. officinarum and applied to comparative pharmacokinetic, tissue distribution and excretion studies. Our results clarified that oral administration of A. officinarum produced significant alterations in the pharmacokinetic parameters of indomethacin. And the pharmacokinetic interaction between indomethacin and A. officinarum reduced the systemic exposure of indomethacin and increased its elimination. Tissue distribution results demonstrated that co-administration of A. Officinarum could not reduce the accumulation of indomethacin in the target tissue of the stomach, but could accelerate the excretions of indomethacin and its three metabolites including ODI, NDI and IDAb G in the bile and feces of rats in the excretion study.Therefore, A. Officinarum might have a gastrointestinal protective effect through the interaction role with indomethacin based on the pharmacokinetics and excretion in rats.

Morphological observation of endometrium in rats and rabbits after insertion of indomethacin-Cu-IUD

Objective: To investigate the effect of indomethacin-Cu-IUD on the endometrium. Methods: Four kinds of IUDs were inserted into the uteri of rats and rabbits through laparotomy. The animals were killed at 1,3,6 months after treatment and their uteri were taken for histological examination with either microscopy and transmission electron microscopy. The rats and rabbits without IUD served as control. Results: There was no obvious pathological change in indomethacin-Cu-IUD group at 1-6 months after insertion of IUD, similar to the control. There were some mild edema and hyperplasia of fibrous tissues in endometrium in Cu-IUD group. There was a significantly change in the vessels of microcirculation. Most vessels were normal or contracted in the indomethacin--Cu--IUD group (75 % ) and control group(87% ), while most vessels were dilated in the Cu-IUD group(70% ) (P<0. 01 ). Conclusion: Indomethacin--Cu-IUD has no harmful effect on endometrium.

EFFECT OF INDOMETHACIN ON SEPTIC SHOCK:EXPERIMENTAL AND PRELIMINARY CLINICAL TRIALS

Twenty-four rabbits were randomly divided into two groups: indomethacin group (Group A, n=12) and control group (Group B, n=12). Rabbits in septic shock had profound hypotension, hypoxia, leukocytopenia, thrombocytopenia, increased levels of lactate and prostaniods. Indomethacin (3 mg/kg) given 10 minutes after the occurrence of shock significantly improved the 24-hour survival of animals, rapidly reversed the hypotensive state of shock, increased the arterial oxygen pressure, partly prevented the increase of blood lactate, and decreased the level of prostaniods. Preliminary clinical trials also showed that indomethacin decreased the level of prostaniods and raised the blood pressure in pediatric patients with septic shock. It is clear that further clinical study is warranted.

Effect of IUD with Indomethacinon Rabbits Endometrium by Enzyme Histochemistry

The present paper reported the observation of the effect of IUD with indomethacin on enzyme activities of succinic dehydrogenase(SDH),nonspecific esterase(NSE)and ATPase in endomtrium of rabbits,and the comparison with copper intrauterine devices,silicon rubber and IUD with copper and indomethacin.The results indicated:1.In the group of indomethacin,the enzyme activities of SDH,NSE and ATPase were increased,while they were obviously decreased in IUD with copper.In the group of IUD with copper and indomethacin the enzyme activities also decreased,but were higher than those observed in the silicon rubber group.2.The damage to endometrium was obvious in IUD with copper.The damage to epithelium of endometrium in structure and function by IUD with indomethacin was found to be lower.

Different cell kinetic changes in rat stomach cancer after treatment with celecoxib or indomethacin: Implications on chemoprevention

AIM: Mechanisms underlying the chemopreventive effects of cyclooxygenase (COX) inhibitors remain elusive. We have previously shown that celecoxib but not indomethacin could prevent carcinogen-induced gastric cancer development in Wistar rats. This chemopreventive effect appeared to be independent of COX-2 and prostaglandin (PG) E2 suppression since the lowest PGE2 was obtained in indomethacin group.This study compared the cell kinetic changes in stomachs of rats after treatment with celecoxib (5, 10, 20 mg/(kg·d)) or indomethacin (3 mg/(kg·d)) to gain more insights into the chemopreventive mechanism.METHODS: The apoptosis and proliferation indexes in gastric tumor, adjacent non-cancer tissues and normal gastric tissues were determined. Apoptosis was quantified by apoptotic nuclei counting and TUNEL, whereas proliferation was determined by Ki67 immunostaining.RESULTS: Treatment with either celecoxib or indomethacin inhibited gastric tumor proliferation by more than 65% (P＜0.02). However, celecoxib caused a dose-dependent increase in apoptosis (P＜0.05) which was not seen in indomethacin-treated tumors (P = 0.54). The highest apoptosis to proliferation ratio was seen in tumors treated with celecoxib at 10 mg/(kg·d). Treatment with this dose of celecoxib was associated with the lowest incidence of gastric cancer development.CONCLUSION: Our findings suggest that the difference in chemopreventive effects of indomethacin and celecoxib in this animal model of gastric carcinogenesis is largely due to the differential cell kinetic changes, which does not correlate with the degree of COX-2 and PG suppression.

Indomethacin suppresses growth of colon cancer via inhibition of angiogenesis in vivo

AIM: It has been reported that regular consumption of nonsteroidal anti-inflammatory drugs like indomethacin decreases the incidence and mortality rate of a number of gastrointestinal cancers. We aimed to explore the efficacy and possible mechanisms of indomethacin on tumor growth and tumor angiogenesis of human colon cancer xenografts in nude mice,METHODS: MTT (thiazolyl blue) assay was used to assess the effect of indomethacin on cultured human colorectal cancer cell line HCT116. HCT116 cells were inoculated subcutaneously into BALB/c-nu/nu mice. After oral administration of indomethacin, 3 mg/kg·d for 4 wk, animals were sacrificed by cervical dislocation. Immunohistochemical staining was employed to determine the microvessel density (MVD) and vascular endothelial growth factor (VEGF)expression in tumor tissues.RESULTS: Indomethacin, a non-selective COX inhibitor,significantly decreased the viability of HCT116 cells in a dose-dependent manner (P＜0.05) with 50% inhibition at approximately 318.2±12.7 μmol/L. Growth of HCT116 cell tumor was significantly suppressed by indomethacin. The tumor volume was significantly decreased in the treated group (458.89±32.07 mm3) compared to the control group (828.21±31.59 mm3) (P＜0.05). The MVD of the treated group (19.50±5.32) was markedly decreased compared to the control group (37.40±4.93) (P＜0.001). The VEGF expression of the treated group (1.19±0.17) was obviously reduced as compared to the control group (1.90±0.48)(P＜0.01). The decrease in MVD was positively correlated with the decrease of VEGF expression (rs = 0.714, P＜0.05).We did not see gastrointestinal complications in the treated group and no differences were noted in the body weight of the mice between the two groups throughout the study (P＞0.05).CONCLUSION: Indomethacin can significantly decrease the viability of cultured HCT116 cells and retard human colorectal HCT116 cell tumor growth via inhibiting tumor angiogenesis, which might be through reduction of VEGF expression.

Is rectal indomethacin effective in preventing of post-endoscopic retrograde cholangiopancreatography pancreatitis?

AIM:To investigate the effectiveness of rectally administered indomethacin in the prophylaxis of post-endoscopic retrograde cholangiopancreatography(ERCP)pancreatitis and hyperamylasaemia in a multicentre study.METHODS:A prospective,randomised,placebocontrolled multicentre study in five endoscopic units was conducted on 686 patients randomised to receive a suppository containing 100 mg indomethacin,or an inert placebo,10-15 min before ERCP.Post-ERCP pancreatitis and hyperamylasaemia were evaluated 24 h following the procedure on the basis of clinical signs and laboratory parameters,and computed tomography/magnetic resonance imaging findings if required.RESULTS:Twenty-one patients were excluded because of incompleteness of their data or because of protocol violation.The results of 665 investigations were evaluated:347 in the indomethacin group and 318 in the placebo group.The distributions of the risk factors in the two groups did not differ significantly.Pancreatitis developed in 42 patients(6.3%):it was mild in34(5.1%)and severe in eight(1.2%)cases.Hyperamylaesemia occurred in 160 patients(24.1%).There was no significant difference between the indomethacin and placebo groups in the incidence of either postERCP pancreatitis(5.8%vs 6.9%)or hyperamylasaemia(23.3%vs 24.8%).Similarly,subgroup analysis did not reveal any significant differences between the two groups.CONCLUSION:100 mg rectal indomethacin administered before ERCP did not prove effective in preventing post-ERCP pancreatitis.

Protective Effect of Holothurian Intestine Against Indomethacin Induced Gastric Mucosal Damage in Rats

Our study aimed to investigate the protective effects of Holothurian intestines(HI) on NSAIDs-induced gastric mucosal damage and the possible mechanism. At first, 60 male Wistar rats were induced of gastric lesions with indomethacin(IDM, 30 mg kg^(-1)). The rats were pretreated for 15 consecutive days with saline, sucralfate, or HI(0.4g kg^(-1) d-1, 0.8 g kg^(-1) d^(-1) and 1.6 g kg^(-1) d^(-1)) prior to IDM treatment, followed by evaluations of macroscopic damage and microscopic features; and investigation of the levels of inflammatory cytokines, oxidative stress parameters, gastric mucosal prostaglandin E2(PGE2) and total hexosamine in tissues. The expression of COX-1 and COX-2 m RNA in the gastric tissue were determined by quantitative polymerase chain reaction(q PCR). Pathological gastric ulcer indexes, levels of pro-inflammatory cytokines(IL-1β, IL-17, TNF-α) and lipid peroxidation were significantly decreased in HI-treated groups, whereas the levels of protective factors(TGF-β, GSH, SOD activity and PGE2) were significantly elevated especially in the group with HI 1.61 g kg^(-1) d^(-1)(P < 0.05). Furthermore, the expression of COX-2 mRNA decreased significantly in HI groups(P < 0.05). The study investigates that holothurian intestines may act as a kind of marine medicine which have protective effect on IDM-induced gastric ulcer, which could be a dietary preventive agent for the prevention of gastric damage.

Irsogladine maleate suppresses indomethacin-induced elevation of proinflammatory cytokines and gastric injury in rats

AIM: To investigate the mucosal protective effect and the mechanisms of action of the anti-ulcer drug irsogladine maleate in gastric injury induced by indomethacin in rats. METHODS: Gastric mucosal injury was induced in male Hos:Donryu rats by oral administration of indomethacin at a dose of 48 mg/kg. One hour before indomethacin treatment, animals were orally pretreated with irsogladine maleate at doses of 1 mg/kg, 3 mg/kg or 10 mg/kg. Four hours after indomethacin administration, the animals were sacrificed and their stomachs were rapidly removed and processed for the evaluation of gastric mucosal damage and the determination of the concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-8 and myeloperoxidase (MPO) in mucosal tissues. RESULTS: Linear hemorrhagic mucosal lesions were observed primarily in the glandular stomach 4 h after oral administration of indomethacin. Pretreatment with irsogladine maleate markedly reduced the number and severity of these lesions in a dose- dependent manner. The mucosal concentrations of proinflammatory cytokines (TNF-α, IL-1β, and IL-8) and MPO, which indicates the degree of mucosal infiltration by neutrophils, increased concomitantly with the occurrence of gastric injury in the indomethacin- treated rats. Pretreatment with irsogladine maleate significantly decreased the levels of these inflammatory factors in gastric tissue elicited by indomethacin.CONCLUSION: The mucosal protective effects afforded by irsogladine maleate on gastric injury induced by indomethacin are mediated by inhibition of mucosal proinflammatory cytokine production and neutrophil infiltration, leading to suppression of mucosal inflammation and subsequent tissue destruction.